Effects of PrEP Drugs on Female Genital HIV Infection and Women's Reproductive Health

PrEP药物对女性生殖器HIV感染及妇女生殖健康的影响

• 批准号: 10703238
• 负责人: Ashley F George
• 金额: $ 12.66万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-14 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10703238
• 关键词: 3-Dimensional; AIDS prevention; Academia; Adherence; Adverse effects; Affect; Age; Anatomy; Antibodies; Award; Biological; Biological Assay; Biopsy; Blood; CD4 Positive T Lymphocytes; California; Cells; Coculture Techniques; Coitus; Communicable Diseases; Complex; Dapivirine; Data; Decidual Cell Reactions; Development; Development Plans; Effector Cell; Endocervix; Endometrial; Endometrium; Environment; Exocervix; Female; Female genitalia; Fertility; Fibroblasts; Gastrointestinal tract structure; Goals; Gonadal Steroid Hormones; HIV; HIV Infections; Health; Heterosexuals; Immune; Immunophenotyping; Impairment; In Vitro; Infection; Infection prevention; Inflammation; Integrase Inhibitors; Interferons; Invaded; Knowledge; Life; Maintenance; Methods; Modeling; Monitor; Mucous Membrane; Mus; Natural Killer Cells; Organoids; Ovarian hormone; Periodicity; Pharmaceutical Preparations; Phenotype; Physiological; Play; Predisposition; Pregnancy; Pregnancy Complications; Process; Progesterone; Public Health; Regimen; Reporting; Reproductive Health; Reproductive Immunology; Reproductive Process; Reproductive Tract Infections; Research; Research Personnel; Research Proposals; Resources; Reverse Transcriptase Inhibitors; Risk; Role; San Francisco; Seminal fluid; Signal Transduction; Socioeconomic Factors; Spiral Artery of the Endometrium; Surface; System; Tenofovir; Testing; Training; Universities; Uterus; Viral; Woman; Women' s Health; aged; career; career development; cell type; design; experimental study; fetal; immune activation; in vivo; infection rate; inflammatory milieu; inhibitor; insight; men who have sex with men; microbiome composition; mouse model; multiple omics; natural Blastocyst Implantation; peripheral blood; permissiveness; pre-exposure prophylaxis; prevent; prophylactic; reproductive; reproductive system disorder; reproductive tract; sexual HIV transmission; single-cell RNA sequencing; tissue culture; tool; transcriptome; transmission process; trophoblast; vaginal microbiome; virology; young woman

PROJECT SUMMARY Worldwide, young reproductive age women account for the majority of new HIV infections, which is often transmitted through heterosexual intercourse. Pre-exposure prophylactic (PrEP) drugs have been highly effective in preventing HIV transmission in men who have sex with men (MSM). However, PrEP efficacy in women has been much more variable, which has been attributed to societal reasons, low adherence, and due to biological and anatomical differences of the female reproductive tract (FRT) relative to the gastrointestinal (GI) tract. A number of FRT mucosal factors – including FRT fibroblasts, factors in semen, and inflammation – can increase HIV infection rates. These same factors can also diminish the anti-HIV activity of PrEP drugs. As many women at risk of HIV are of reproductive age, it is also important to determine the extent to which PrEP may affect fertility. Indeed, some PrEP drugs have been reported to impair processes essential for pregnancy. PrEP has also been shown to elicit interferon signaling in mucosal tissues, which could affect the functions of FRT T and Natural Killer (NK) cells. Of note, T and NK cells are effector cells that play critical roles in both viral defense and pregnancy. These observations suggest a better understanding of PrEP within the FRT microenvironment, and of potential adverse effects of PrEP on pregnancy, is needed. I am pursuing the K99 Award in order to gain further training to meet my long-term career goals: to become an independent investigator conducting research on infectious diseases and reproductive disorders affecting women. The environment at Gladstone Institutes and the University of California at San Francisco are exceptional and will provide the essential resources to successfully complete my career development plan and achieve my career goals. The objective of this research proposal is to determine how the environment of the FRT can influence PrEP efficacy, and conversely how PrEP can influence the FRT to affect fertility. My hypothesis is that FRT mucosal factors adversely affect the anti-HIV activities of PrEP, and that some but not all PrEP regimens can disrupt FRT processes important for pregnancy. In Aim 1, I will use FRT infection models and CyTOF to determine how the activity of PrEP is affected by the environment of the FRT mucosa. In Aim 2, I will use ex vivo tissue culture and organoid models, as well as in vivo mouse models, to determine how PrEP drugs affect pregnancy and processes important for pregnancy establishment and maintenance. In Aim 3, I will use multi-omics approaches to characterize T and NK cells from FRT of HIV-seronegative, reproductive-age women who are on or off PrEP, in order to assess to what extent PrEP alters the phenotypes of these cells. Identifying the mechanisms underlying HIV infection of susceptible cells in FRT in the context of suboptimal concentrations of PrEP (which is more common in the FRT than in the GI tract) will be crucial for the development of effective PrEP that young women can safely use without worrying about potential pregnancy complications. This could dramatically reduce the rate of transmission in reproductive- age women and have a significant impact on global public health.

项目摘要 全球，年轻的生殖年龄女性占多数新的艾滋病毒感染，这通常是 通过异性交往传播。暴露前预防性（PREP）药物已高度 有效防止与男性发生性关系的男性（MSM）的艾滋病毒传播。但是，准备效率 妇女的变化要多得多，这归因于社会原因，依从性低和应有的 相对于胃肠道（GI），女性生殖道（FRT）的生物学和解剖学差异 道。许多FRT粘膜因子（包括FRT成纤维细胞，精液中的因素和炎症）可以 提高艾滋病毒感染率。这些相同的因素也可以减少PREP药物的抗HIV活性。就像许多 患有艾滋病毒风险的妇女是生殖年龄，确定PREP可能的程度也很重要 影响生育能力。实际上，据报道，一些预备药物会损害怀孕必不可少的过程。准备 还显示出在粘膜组织中引起干扰素信号传导，这可能会影响frt t的功能 和天然杀手（NK）细胞。值得注意的是，T和NK细胞是在两个病毒防御中起关键作用的效应细胞 和怀孕。这些观察结果表明，对FRT微环境中的准备有更好的理解， 并且需要准备对怀孕的潜在不利影响。我正在寻求K99奖，以获取 进一步培训以实现我的长期职业目标：成为一名独立研究者进行研究 关于影响妇女的传染病和生殖疾病。 Gladstone Institutes和 加利福尼亚大学旧金山分校非常出色，将为 成功完成我的职业发展计划并实现我的职业目标。这项研究的目的 建议是确定FRT的环境如何影响准备效率，相反 可以影响FRT影响生育能力。我的假设是，FRT粘膜因子对抗HIV产生不利影响 准备活动，某些但并非所有的准备方案可能会破坏对怀孕重要的FRT过程。 在AIM 1中，我将使用FRT感染模型和细胞来确定PREP的活动如何受到 FRT粘膜的环境。在AIM 2中，我将使用离体组织培养和类器官模型，以及 体内小鼠模型，确定准备药物如何影响怀孕和对怀孕重要的过程 建立和维护。在AIM 3中，我将使用多摩管的方法来表征T和NK细胞的 艾滋病毒 - 副作用，生殖年龄妇女的妇女正在开放或关闭准备，以评估在多大程度上 PREP改变了这些细胞的表型。确定易感的HIV感染的机制 在次优浓度的PREP的情况下，FRT中的细胞（在FRT中比在FRT中更常见 胃肠道）对于年轻女性可以安全使用而不必担心的有效准备的开发至关重要 关于潜在的怀孕并发症。这可能会大大降低生殖 - 妇女年龄，对全球公共卫生有重大影响。